Investigations of human exposure to environmental contaminants were funded by this research budget in FY2015 as follows: 1) Anniston community health survey (ACHS-II): Follow-up study and dioxin analyses. This is a major cross-sectional epidemiology investigation in residents of Anniston, Alabama exposed over time to PCBs and other contaminants from a local chemical production facility. A previous study conducted by the Agency for Toxic Substances and Disease Registry (ATSDR) of the Centers for Disease Control (CDC) found elevated blood levels of PCBs in the population associated with a high incidence of hypertension and diabetes. The current study partners with ATSDR to assess current blood concentrations of non-dioxin-like and dioxin-like PCBs, other dioxin-like chemicals, and heavy metals in some participants of the earlier study. The results will be used for health and risk management for the exposed individuals. The recruitment and sampling phases of this study are concluded. Blood was collected from 359 of 777 subjects from the original study. Laboratory analysis of these samples is underway. Preliminary results from some participants indicate a decrease over time in serum levels of many PCB congeners, especially those of lowest chlorination. A journal article outlining the details and methods of the present study was published in FY2015. New research is underway to assess the degree of DNA methylation (biomarker of chemical exposure) in these subjects. 2) Toxic organic chemicals and heavy metals in blood and urine of electronic waste recycling workers and the general population in rural Vietnam. This collaborative study with Vietnamese researchers and others compares concentrations of heavy metals, PCBs, dioxins, and other POPs in e-waste recyclers and a control cohort. Sample analysis conducted in FY2015 detected elevated levels of some organic pollutants in the workers and of some heavy metals in subjects from both cohorts. 3) The determination of POPs and their metabolites in brain tissue and ventricular fluid. This study seeks to establish a correlation with POPs exposure to neurological disorders in humans. The collaborative study is being conducted by researchers from Duke University and the National Toxicology Program (NTP). Sample analysis was underway in FY2015. 4) Bisphenol A (BPA) pharmacokinetics: Controlled exposure study. This study is being conducted in collaboration with NIEHS and NTP researchers. The results for an oral exposure to 14 subjects were published in FY2015. Dermal application studies are in progress. These data will be used for further understanding of the fate of this potential endocrine disruptor in humans. Studies of the fate and toxicity of several brominated flame retardants (BFRs) were conducted in the PI's research laboratory in FY2015 as follows: 1) Studies of the major flame retardant tetrabromobisphenol A (TBBPA). Wistar Han rats chronically exposed to TBBPA by the oral route have a higher incidence of uterine tumors than in controls. Studies were designed to characterize this mechanism of toxicity. A study of the fate of TBBPA in female rats did not detect evidence for accumulation of TBBPA or generation of TBBPA-derived reactive metabolites in uterine tissues. Therefore, the most likely hypothesis for the carcinogenic response involved disruption of estrogen homeostasis in the TBBPA-exposed rats. This hypothesis was subsequently supported by the results of molecular studies conducted in the laboratory. A manuscript of these results has been prepared and submitted for publication. Humans are at risk for dermal exposure to TBBPA; therefore, a study was conducted with USEPA researchers for the purpose of predicting bioavailability of TBBPA in humans. This was accomplished by comparing results of TBBPA dermal exposure in intact rats with that of in vitro exposure to rat and human skin. These studies are completed and a manuscript of the results has been submittedfor publication. Humans may also be at risk for developmental exposure to low-doses of TBBPA in the environment. Data are needed in a rodent model for extrapolation purposes; therefore, a collaborative study of prenatal and perinatal exposure to TBBPA in rats is being conducted with other NIEHS researchers. 2) Studies of novel and emerging BFRs. Some legacy BFRs, e.g. polybrominated diphenyl ethers (PBDEs), have accumulated in the environment, wildlife, and humans. These BFRs are being replaced with newer brominated chemicals such as 1-ethylhexyl-2,3,4,5-tetrabromobenzoate (TBB), di(2-ethylhexyl)tetrabromophthalate (TBPH), and decabromodiphenyl ethane (DBDPE). However, adequate toxicological evaluations for these chemicals are lacking. Toxicokinetic studies are being conducted in this laboratory to provide supporting data for designing and interpreting toxicity studies and risk assessments for these chemicals. These studies presently include investigations of the fate of each chemical in rodents by different exposure routes, with emphasis on determining bioavailability, detoxication and activation pathways, target tissues and accumulation potential, and rates and routes of dose excretion. Preliminary results of these studies were reported at scientific meetings in FY2015 and journal articles of completed studies are in preparation. Additional studies are being designed as needed. In addition to the studies previously described, the PI of this laboratory contributed time and effort as a co-contributor to other works associated with the research goals of this project. In FY2015, this research project also funded development of PBPK models of rodent data in rodents for extrapolation to human risk assessment efforts.